多尺度 3D 基因组组织是 ILC2 发生和过敏性气道炎症的基础。
Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation.
机构信息
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
出版信息
Nat Immunol. 2023 Jan;24(1):42-54. doi: 10.1038/s41590-022-01295-y. Epub 2022 Sep 1.
Innate lymphoid cells (ILCs) are well-characterized immune cells that play key roles in host defense and tissue homeostasis. Yet, how the three-dimensional (3D) genome organization underlies the development and functions of ILCs is unknown. Herein, we carried out an integrative analysis of the 3D genome structure, chromatin accessibility and gene expression in mature ILCs. Our results revealed that the local 3D configuration of the genome is rewired specifically at loci associated with ILC biology to promote their development and functional differentiation. Importantly, we demonstrated that the ontogenesis of ILC2s and the progression of allergic airway inflammation are determined by a unique local 3D configuration of the region containing the ILC-lineage-defining factor Id2, which is characterized by multiple interactions between the Id2 promoter and distal regulatory elements bound by the transcription factors GATA-3 and RORα, unveiling the mechanism whereby the Id2 expression is specifically controlled in group 2 ILCs.
先天淋巴细胞 (ILC) 是一种特征明确的免疫细胞，在宿主防御和组织动态平衡中发挥关键作用。然而，三维 (3D) 基因组结构如何为 ILC 的发育和功能奠定基础尚不清楚。在此，我们对成熟 ILC 中的 3D 基因组结构、染色质可及性和基因表达进行了综合分析。我们的结果表明，与 ILC 生物学相关的基因组局部 3D 结构会发生特定的重排，以促进其发育和功能分化。重要的是，我们证明了 ILC2 的个体发生和过敏性气道炎症的进展取决于包含 ILC 谱系定义因子 Id2 的区域的独特局部 3D 结构，其特征是 Id2 启动子与转录因子 GATA-3 和 RORα 结合的远端调控元件之间存在多个相互作用，揭示了 Id2 表达在 2 型 ILC 中特异性调控的机制。
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